Sequence-graph based tool for determining variation in short tandem repeat regions

By employing sequence graphs with self-loops and probabilistic modeling, the method addresses the challenge of aligning short reads to repeat sequences, effectively identifying medically relevant repeat expansions in genetic disorders.

US12374422B2Active Publication Date: 2025-07-29ILLUMINA INC
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Patent Information

Application Number
US16/811919
Authority / Receiving Office
US · United States
Patent Type
Patents(United States)
Current Assignee / Owner
Priority Date
2019-03-07
Filing Date
2020-03-06
Publication Date
2025-07-29
Estimated Expiration
2042-08-25

AI Technical Summary

Technical Problem

Existing methods struggle to accurately identify medically relevant repeat expansions using short reads that do not fully traverse the repeat sequence, due to challenges in aligning and mapping these reads to reference sequences.

Method used

The use of sequence graphs with self-loops representing repeat sequences, combined with probabilistic modeling and alignment techniques, allows for the genotyping of repeat sequences, even with incomplete or short reads, by aligning reads to directed graphs and determining genotypes using paired end reads.

Benefits of technology

This approach enables precise identification of repeat expansions associated with genetic disorders, such as Fragile X syndrome and Huntington's disease, by accurately determining genotypes of repeat sequences, even when reads are shorter than the repeat sequences.

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Abstract

The disclosed embodiments concern methods, apparatus, systems and computer program products for genotyping repeat sequences such as medically significant short tandem repeats (STRs). The methods involve aligning reads to a repeat sequence represented by a sequence graph, and using the aligned reads to genotype the repeat sequence. The sequence graph is a directed graph each including at least one self-loop representing a repeat sub-sequence. In some implementations, the reads are paired end reads, and both mates of each read pair may be used to genotype the repeat sequences. Some implementations can be used to determine degenerate codon repeats. Some implementations can be used to genotype repeat sequences each including two or more repeat sub-sequences. Some implementations can be used to genotype nucleic acid sequences each including at least one repeat sub-sequence and another genetic variant such as an insertion, deletion, or substitution.
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